This is a low grade B-cell non-Hodgkin's lymphoma (NHL). It is a neoplastic proliferation of small mature lymphocytes and shares a clinical overlap with cases of chronic lymphocytic leukemia (CLL). In fact, if a patient has an absolute lymphocytosis of >5000/mm3 in the peripheral blood, CLL is diagnosed, regardless of the findings in the lymph node.
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EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Precursor B-Lymphoblastic Leukemia/lymphoma INCIDENCE 5% of NHLs AGE RANGE-MEDIAN Median 60 years SEX (M:F) Equal
PATHOGENESIS CHARACTERIZATION Chromosomes Trisomy 12
Aberrations of chromosomes 6 and 13
HISTOLOGICAL TYPES CHARACTERIZATION Lymphocytes
Clumped nuclear chromatin exhibiting a compartmentalization phenomenon
May vary from medium to large size
Diffuse and dark blue staining lymphoid tissue on low power magnification
Scattered throughout are pale staining, rounded non-expansile foci representing proliferation centers (pseudofollicles)-DIAGNOSTIC of B-CLL/SLL
Pale foci composed of small to medium-sized cells with distinct nucleoli (prolymphocytes and paraimmunoblasts) with a background of small lymphocytes
Peripheral blood Lymphocytosis <5000/mm3 VARIANTS GRANULOMAS
Necrotizing granulomas in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma.
Blanco M, Ratzan J, Cabello-Inchausti B, Fernandes L.
Arkadi M. Rywlin, MD Department of Pathology and Laboratory Medicine and the Comprehensive Cancer Center, Mt Sinai Medical Center of Greater Miami, Miami Beach, FL.
Ann Diagn Pathol 2002 Aug;6(4):216-21 Abstract quote
We present three cases of patients with B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia that were retrieved from our files during a period of 11 months and who suddenly developed lymphadenopathy.
Clinically, this lymphadenopathy was thought to represent a manifestation of their background disease and, for this reason, no cultures were performed on fresh tissue. However, histologic studies in all cases showed necrotizing granulomas. When results of our special stains were negative, we submitted the specimens for molecular studies, which demonstrated the presence of tuberculous bacilli in two out of three cases.
We believe that tuberculosis can present as a sudden lymphadenopathy in immunocompromised people and we would like to raise the awareness among the clinicians and nursing and pathology laboratory staff about the risks of handling these specimens without proper precautions. Also, we emphasize the fact that, in some cases, tuberculous bacilli cases may need molecular studies to be demonstrated.
Interfollicular small lymphocytic lymphoma Residual follicles may be numerous spared by an interstitial infiltrate of neoplastic lymphocytes PARAIMMUNOBLASTIC
Paraimmunoblastic variant of small lymphocytic lymphoma/leukemia.
Pugh WC, Manning JT, Butler JJ.
Department of Pathology, University of Texas M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Am J Surg Pathol 1988 Dec;12(12):907-17 Abstract quote
We report 16 cases of a distinctive, biologically aggressive variant of small lymphocytic lymphoma/leukemia (SLL/L) that is characterized by the diffuse proliferation of cells normally comprising the pseudoproliferation centers (so-called paraimmunoblasts).
Demographically, the patients differed in no significant regard from patients with SLL/L of usual type. Rapidly progressive, generalized lymphadenopathy was the dominant clinical finding in 15 of the 16 patients; one patient presented with symptoms related to lymphomatous involvement of the stomach and regional lymph nodes. Splenomegaly was observed in five patients. Seven patients, two of whom had a history of indolent-phase chronic lymphocytic leukemia, had an absolute lymphocytosis at diagnosis.
In most patients, bone marrow involvement was noted at diagnosis. It consisted predominantly of small lymphocytic infiltrates indistinguishable from those observed in SLL/L of usual type; significant paraimmunoblastic infiltration was infrequent and generally occurred late in the disease course. Immunohistochemical and cytogenetic study further substantiated the hypothesized relationship of these cases to SLL/L. Findings included (a) coexpression of sIg and Leu-1 antigen in the majority of cases and (b) the presence of a t(11;14) (q13;q32) chromosome translocation in two of three cases with analyzable metaphases.
Although treatment protocols were not uniform, follow-up data indicated an accelerated clinical course. Eleven patients have died of their disease between 3 and 39 months after diagnosis; the median survival was 28 months.
Genetic characterization of the paraimmunoblastic variant of small lymphocytic lymphoma/chronic lymphocytic leukemia: A case report and review of the literature.
Espinet B, Larriba I, Salido M, Florensa L, Woessner S, Sans-Sabrafen J, Barranco C, Serrano S, Sole F.
Laboratori de Citogenetica i Biologia Molecular, Departament de Patologia, Escola de Citologia Hematologica Soledad Woessner-IMAS, Barcelona, Spain.
Hum Pathol 2002 Nov;33(11):1145-8 Abstract quote
Paraimmunoblastic variant of small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) is characterized by a diffuse proliferation of cells, called paraimmunoblasts, normally located on the pseudoproliferation centers. Patients usually present with multiple lymphadenopathies and a rapid and aggressive progression of the disease.
We report a case with paraimmunoblastic variant of SLL/CLL genetically well-characterized by conventional cytogenetics, comparative genomic hybridization (CGH), IgH/BCL-1, IgH/BCL-2, and p53 fluorescent in situ hybridization (FISH) probes and polymerase chain reaction (PCR) for detection of IgH/BCL-2 translocation. A complex karyotype was found, with p53 deletion confirmed by CGH and FISH; however, no translocations involving either BCL-2 or BCL-1 and the immunoglobulin heavy chain gene were identified.
A literature review shows only 20 previously reported cases, 6 of which involve genetic studies.
Hum Pathol. 2006 Feb;37(2):152-9. Epub 2006 Jan 10. Abstract quote
Prognostication in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) based, in part, on ZAP-70 and CD38 expression, and to a lesser extent, on MUM1/IRF4 expression, is currently of great interest. The more aggressive type of CLL/SLL is reportedly characterized by neoplastic cells that are more responsive to B-cell signaling with proliferation centers (PCs), a potentially important site of neoplastic cell stimulation.
To study the relationship of these markers to each other and to the pattern of PCs, immunohistochemical stains for ZAP-70 and MUM1/IRF4 were performed and the PC patterns assessed (where possible) in 29 tissue biopsies with CLL/SLL. CD38 expression was assessed in 18 cases using flow cytometry. Ten evaluable cases had a typical PC pattern and 16 an atypical pattern with larger or more confluent PCs and/or more numerous paraimmunoblasts/transformed cells. ZAP-70 was positive in 14 of 28 cases, including 3 with atypical PCs and enhanced PC staining. All 29 cases showed MUM1/IRF4 expression in PCs. Seven cases, none with atypical PC, also showed uniform positivity throughout, 14 showed weaker staining of surrounding lymphocytes, and 8 had PC staining only. CD38 was positive in 14 of 18 cases. The only significant association identified was between uniform MUM1/IRF4 positivity and typical PCs (P = .004).
These findings highlight the complex interrelationship of prognostic markers in CLL/SLL and demonstrate potentially important microenvironmental variations in their expression. They support the hypothesis that PCs are a site for B-cell receptor signaling, which helps explain reported site-dependent antigenic variation in CLL/SLL, and suggest that PC morphology may correlate with other biological features.
Immunophenotype does not correlate with lymph node histology in chronic lymphocytic leukemia/small lymphocytic lymphoma.
Asplund SL, McKenna RW, Howard MS, Kroft SH.
University of Texas Southwestern Medical School, Dallas, Texas, USA.
Am J Surg Pathol 2002 May;26(5):624-9 Abstract quote
The presence of prominent proliferation centers (PCs) in lymph nodes (LNs) involved with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has been associated with atypical blood smear morphology. Atypical CLL has in turn been associated with variant immunophenotypes and poor outcome. However, the significance of abundant PCs remains controversial.
We have analyzed the flow cytometric immunophenotypic features of 54 CLL/SLL LNs and correlated these findings with the morphologic and clinical features. The LN histology was assigned to one of two groups based on the prominence of PCs: Group I LNs contained scattered small, sometimes ill-defined PCs in a background of monotonous small round lymphocytes. Group II LNs had increased numbers and sizes of PCs resulting in an obviously nodular appearance at low magnification. Flow cytometry was performed using broad three- or four-color antibody panels that included anti-CD5, CD19, CD20, CD23, CD38, FMC7, and surface immunoglobulin (sIg). The intensity of expression of all markers was scored semi-quantitatively using isotypic controls and internal positive and negative populations as standards.
There were 32 group I and 22 group II LNs that, by definition, expressed CD19, CD5, and CD23. Little variability was seen in the intensity of expression of CD19, and the majority of cases expressed CD23 brightly. CD5 varied from very dim to an intensity similar to that of normal T cells; the majority had an intermediate level of CD5 expression. FMC7 was expressed to a significant extent in 11 cases (21%). CD20 was relatively bright in 17 cases (32%). sIg was dim in 29 cases (55%) and moderate or bright in 24 cases (45%). CD38 was expressed significantly in 25 cases (47%). There was no correlation between histologic group and intensity of expression of any individual marker or with an immunophenotypic atypia score based on FMC7, CD20, and sIg.
There was also no correlation between morphology or immunophenotype and clinical features. These findings do not support the interpretation that the prominence of proliferation centers in CLL/SLL LNs defines biologically distinct subtypes.
CHARACTERIZATION Positive Surface Ig (mostly IgM)
Weak Expression CD5, CD19, CD20, and CD23 Negative Lack of expression of CD10 and CD22 GENERAL Comparison of Immunophenotypes of Small B-Cell Neoplasms in Primary Lymph Node and Concurrent Blood or Marrow Samples
Yin Xu, MD, PhD, Robert W. McKenna, MD, Sheryl L. Asplund, MD, and Steven H. Kroft, MD
Am J Clin Pathol 2002;118:758-764 Abstract quote
Immunophenotyping of small B-cell neoplasms (SBCNs) may have a critical role in diagnosis. However, there are few data addressing whether the immunophenotypes of SBCNs in bone marrow (BM) and peripheral blood (PB) are representative of those in other tissue sites.
We compared the immunophenotypic features of concurrently analyzed lymph node (LN) and BM/PB specimens using multiparameter flow cytometry. Fifty-five SBCNs were identified: 27 follicular lymphomas (FLs), 16 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLLs), and 12 mantle cell lymphomas (MCLs). Major (presence vs absence) or minor (alteration of intensity) variations in expression of individual antigens between LN and BM/PB were observed in up to 25% of cases within a particular SBCN category.
All FLs and CLL/SLLs maintained characteristic immunopheno-types in BM/PB. Potentially misleading variations included 1 case of MCL that failed to express CD5 in BM and likely would have been immunophenotypically misclassified as a marginal zone lymphoma and another MCL that expressed moderate CD23 in PB and would have required additional studies for precise classification. The remaining major and minor variations would not have affected interpretation.
Assessment of CD10 in the Diagnosis of Small B-Cell Lymphomas A Multiparameter Flow Cytometric Study
Yin Xu, MD, PhD, Robert W. McKenna, MD, and Steven H. Kroft, MD
Am J Clin Pathol 2002;117:291-300 Abstract quote
We evaluated the usefulness of multiparameter flow cytometry with cluster analysis in the diagnosis of a series of 100 well-characterized small B-cell lymphomas (SBCLs).
The histologic diagnoses in the 100 cases were follicular lymphoma (FL) in 58, marginal zone lymphoma (MZL) in 17, small lymphocytic lymphoma in 15, and mantle cell lymphoma (MCL) in 10. Of the 58 FLs, 57 were CD10 positive (98% sensitivity). The 1 negative case was unusual in that it occurred in the small intestine. However, architectural, cytologic, and immunohistochemical features were diagnostic of FL. Of 42 other SBCLs, 2 were CD10+ (95% specificity); 1 was a CD5+/cyclin D1+ MCL, and the other was an extranodal MZL.
We found that assessment of CD10 expression using multiparameter flow cytometry with cluster analysis is highly sensitive and specific for the diagnosis of FL, validating its usefulness in situations in which adequate tissue is not available for definitive histologic diagnosis.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
p27Kip1 Immunostaining for the Differential Diagnosis of Small B-Cell Neoplasms in Trephine Bone Marrow Biopsies
Marcus Kremer, M.D., Stephan Dirnhofer, M.D., Anna Nickl, Heinz Hoefler, M.D., Leticia Quintanilla-Martínez, M.D. and Falko Fend, M.D.
Institute of Pathology (MKHH, FF), Technical University Munich, Germany; Institute of Pathology (SD), University of Innsbruck, Austria; Institute of Pathology (MK, AN, HH, LQM), GSF-National Research Center for Environment and Health, Neuherberg, Germany; and Institute of Pathology (SD), University of Basel, Switzerland.
Mod Pathol 2001;14:1022-1029 Abstract quote
The distinction between mantle cell lymphoma (MCL) and other small B-cell non-Hodgkin lymphomas (NHL) is important because MCL has a more aggressive clinical course. In bone marrow (BM) biopsy specimens, this distinction can be particularly difficult. Although cyclin D1 immunostaining and molecular detection of the t(11;14) translocation are highly specific markers for MCL, they fail to detect a proportion of cases.
We have recently described that MCL typically lacks detectable expression of the cyclin-dependent kinase inhibitor p27kip1 protein by immunostaining, which is expressed at high levels in most small B-cell NHL inversely correlated to the proliferation rate. We therefore examined whether p27kip1 immunostaining could be a useful adjunct for the differential diagnosis of small B-cell NHL infiltrates in the BM.
Trephine BM biopsy specimens of 96 patients, including well-characterized MCL (19 cases), B-cell chronic lymphocytic leukemia (27 cases), follicular lymphoma (18 cases), hairy cell leukemia (22 cases), and marginal zone lymphoma (10 cases) as well as 10 reactive BM, including five with benign lymphoid aggregates were investigated. In addition, the presence of a t(11;14) translocation involving the major translocation cluster was studied by PCR in all MCL. All cases of B-cell chronic lymphocytic leukemia, follicular lymphoma, and marginal zone lymphoma revealed a strong p27kip1 nuclear staining in the majority of neoplastic cells. Fourteen (78%) cases of MCL were p27kip1-negative in the tumor cells, whereas four cases revealed a weak nuclear positivity. Seventeen (77%) cases of hairy cell leukemia were also either completely negative for p27kip1 or showed a faint positive staining in a minority of the neoplastic cells. Nine of 19 cases (47%) of MCL showed a bcl1 rearrangement involving the major translocation cluster region.
These findings demonstrate that p27kip1 immunostaining is a valuable additional marker for the differential diagnosis of small B-cell NHL infiltrates in BM biopsies. The reduction or lack of p27kip1 protein expression in MCL, as well as in hairy cell leukemia, might be an important event in the pathogenesis of these disorders.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS 80% of cases present with pathologic stage IV disease, usually due to bone marrow involvement 5 Year Survival Spontaneous regression in 15% of cases IMMUNOPHENOTYPE Phenotypic Heterogeneity of B Cells in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Bal Kampalath, MD
Maurice P. Barcos, MD, PhD
and Carleton Stewart, PhD
Am J Clin Pathol 2003;119:824-832 Abstract quote
Although some studies have examined the expression of aberrant markers such as CD2, CD7, CD10, CD13, CD33, and CD34 on B cells in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), a uniform multiparametric analysis of the frequency of expression of these markers using stringent criteria is lacking.
By using 3-color flow cytometry, we analyzed 117 cases (bone marrow, 71; blood, 31; lymph nodes, 15) for coexpression of aberrant markers with CD19. Marker expression was considered positive when present on at least 20% of CD19+ cells. Of 117 cases, 40 (34.2%) showed expression of 1 or more aberrant markers. Expression of 4 aberrant markers was seen in 1 case, 3 in 4 cases, 2 in 15 cases, and 1 in 20 cases.
Kaplan-Meier survival curves and the log-rank test revealed that the group with aberrant markers showed significantly shortened overall survival compared with the group without aberrant markers (P < .001).
There is considerable phenotypic heterogeneity in CLL/SLL, and expression of aberrant markers indicates aggressiveness.
Transformation to prolymphocytic leukemia 10-30%
Transformation to large cell lymphoma (Richter's Syndrome) or other aggressive lymphoid malignancies 10-15%
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